Using ultrasound (US)-guided inoculation of the amniotic fluid with the simian immunodeficiency virus (SIV), we have achieved a 86% fetal infection rate in rhesus monkeys (Macaca mulatta). However, neutralizing antibodies developed against HIV-1 cannot be evaluated in this system. Thus, we propose to establish a fetal infection model in macaques using a chimeric virus based on the infectious molecular clone SlVmac239 in which the tat, rev and env sequences of SIV were replaced by homologous sequences of HIV, and into which the vpu sequences of HIV were inserted as welL The resulting chimeric virus, SHIV-vpu+, is infectious in rhesus monkeys. The Specific Aims for this proposal are to: 1. Titrate the dose of SHIV-vpu+ required for reproducible fetal infection via the amniotic fluid. using 8 pregnant M. mulatta late in gestation. The mother/infant pairs will be followed for viremia and disease. 2. Examine a panel of neutralizing human anti-HIV-1 Env monoclonal antibodies (mAbs) for their ability to neutralize SHIV-vpu+. Human mAbs directed against the CD4 binding domain or against the V3 loop will be examined for their activity against SHIV-vpu+ in vitro, singly and in combination regimens. 3. Determine the pharmacokinetics of human mAbs during gestation by weekly injections into pregnant, uninfected macaques. Neutralizing titers in serum, amniotic fluid, cord blood, placental tissues and milk will be determined. Mothers and infants will be examined carefully for signs of toxicity. 4. Test passive immunoprophylaxis with the optimal combination regimen of human anti-HIV mAbs (as determined in Specific Aim #2) during gestation. We anticipate that a combination of mAbs directed against the CD4 binding domain and the V3 loop will be used. Pregnant controls will be treated with irrelevant human mAbs. After pre-treatment, all animals will be challenged with SHIV-vpu + via the amniotic fluid. Moab therapy will be continued until Cesarean section. Mother/infant pairs will be followed for development of viremia and disease. The proposed work is highly significant because it allows in vivo analysis of neutralizing human Moab's directed against the HIV-1 envelope glycoprotein.